Field of the Invention
This invention relates to a pharmaceutical soft gelatin capsule dosage form that may be advantageously used for vaginal administration of a pharmaceutically active ingredient in a muco-adhesively enhanced capsule fill. The soft gelatin capsule dosage form of the invention maintains its shell integrity (hardness) and fill viscosity over the time of storage.
Description of Related Art
Soft gelatin pharmaceutical formulations have several advantages, such as, they are easy to swallow, they mask the odors and unpleasant tastes, and once swallowed, they release their contents very quickly. However, soft gelatin capsules have been known to have a decrease in dissolution during storage, which eventually may retard or deleteriously impact drug release. The decrease in dissolution has typically been attributed to the crosslinking of gelatin in the capsule shell resulting in a pellicle formation. Pellicle formation can be minimized by various techniques such as using excipients in the capsule fill with low grade peroxides and aldehydes, or using gelatin grades less prone to pellicle formation to minimize the formation of crosslinking agents. The manufacturing process can also be optimized, for example, by storing fill under nitrogen, controlling the temperature and humidity of manufacturing environment, minimizing the temperature and heat exposure time of heating processes, testing excipients for formaldehyde or low molecular weight aldehydes levels, and using moisture and/or light resistant packaging.
Applicants have found that even when steps are taken to minimize pellicle formation, soft gelatin capsules containing ionic components such as polyacrylic acid in the fill can exhibit unstable dissolution profiles after storage. It is believed, without being bound by theory, that the polyacrylic acid contained in the fill of the soft gelatin capsule interacts with the gelatin in the shell, inhibiting rupture and thus altering the dissolution profile. Thus, it may be advantageous to provide a soft gelatin capsule dosage form that employs non-ionic components in the fill in order to avoid an unstable dissolution profile after storage.
Vaginal administration of a pharmaceutically active ingredient using a soft gelatin capsule not only requires a stable dissolution profile over storage time, but also requires a fill containing a pharmaceutically active ingredient that maintains a consistent viscosity over time and has muco-adhesive properties that ensure consistent and efficacious application of the active ingredient to the mucosal wall of the vaginal cavity.
Accordingly, it would be advantageous to provide a pharmaceutical soft gelatin capsule dosage form that does not contain ionic components, but which can deliver a low dose drug, such as an estrogen, in a muco-adhesively enhanced fill, while maintaining its shell integrity (hardness) and fill viscosity even after the capsule has been in storage up to one year, preferably 18 months, or more preferably, two years.